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. 1995 May;146(5):1029–1039.

Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.

H F Dvorak 1, L F Brown 1, M Detmar 1, A M Dvorak 1
PMCID: PMC1869291  PMID: 7538264

Abstract

VPF/VEGF is a multifunctional cytokine that contributes to angiogenesis by both direct and indirect mechanisms. On the one hand, VPF/VEGF stimulates the ECs lining nearby microvessels to proliferate, to migrate, and to alter their pattern of gene expression. On the other hand, VPF/VEGF renders these same microvascular ECs hyperpermeable so that they spill plasma proteins into the extravascular space, leading to the clotting of extravasated fibrinogen with deposition of a fibrin gel. Extravascular fibrin serves as a provisional matrix that favors and supports the ingrowth of new blood vessels and other mesenchymal cells that generate mature, vascularized stroma. These same principles apply in tumors, in several examples of non-neoplastic pathology, and in physiological processes that involve angiogenesis and new stroma generation. In all of these examples, microvascular hyperpermeability and the introduction of a provisional, plasma-derived matrix precede and accompany the onset of EC division and new blood vessel formation. It would seem, therefore, that tumors have "borrowed" fundamental mechanisms that developed in multicellular organisms for purposes of tissue defense, renewal, and repair. VPF/VEGF, therefore has taught us something new about angiogenesis; namely, that vascular hyperpermeability and consequent plasma protein extravasation are important, perhaps essential, elements in its generation. However, this finding raises a paradox. While VPF/VEGF induces vascular hyperpermeability, other potent angiogenic factors apparently do not, at least in subtoxic concentrations that are more than sufficient to induce angiogenesis. Nonetheless, wherever angiogenesis has been studied, the newly generated vessels have been found to be hyperpermeable. How, therefore, do angiogenic factors other than VPF/VEGF lead to the formation of new and leaky blood vessels? We do not as yet have a complete answer to this question. One possibility is that at least some angiogenic factors mediate their effect by inducing or stimulating the expression of VPF/VEGF. In fact, there is already one clear example of this. TGF-alpha is a potent angiogenic factor but does not itself increase microvascular permeability. However, TGF-alpha strikingly upregulates VPF/VEGF expression in cultured keratinocytes and is thought to be responsible, at least in part, for the overexpression of VPF/VEGF in psoriasis. Moreover, overexpression of TGF-alpha, along with that of the EGF receptor with which it interacts, is characteristic of many malignant tumors, raising the possibility that TGF-alpha acts to stimulate VPF/VEGF expression in other types of epithelial cells and in this manner induces angiogenesis.(ABSTRACT TRUNCATED AT 400 WORDS)

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andres J. L., Stanley K., Cheifetz S., Massagué J. Membrane-anchored and soluble forms of betaglycan, a polymorphic proteoglycan that binds transforming growth factor-beta. J Cell Biol. 1989 Dec;109(6 Pt 1):3137–3145. doi: 10.1083/jcb.109.6.3137. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Berse B., Brown L. F., Van de Water L., Dvorak H. F., Senger D. R. Vascular permeability factor (vascular endothelial growth factor) gene is expressed differentially in normal tissues, macrophages, and tumors. Mol Biol Cell. 1992 Feb;3(2):211–220. doi: 10.1091/mbc.3.2.211. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Braverman I. M., Keh-Yen A. Three-dimensional reconstruction of endothelial cell gaps in psoriatic vessels and their morphologic identity with gaps produced by the intradermal injection of histamine. J Invest Dermatol. 1986 May;86(5):577–581. doi: 10.1111/1523-1747.ep12355222. [DOI] [PubMed] [Google Scholar]
  4. Braverman I. M., Yen A. Microcirculation in psoriatic skin. J Invest Dermatol. 1974 May;62(5):493–502. doi: 10.1111/1523-1747.ep12681007. [DOI] [PubMed] [Google Scholar]
  5. Breier G., Albrecht U., Sterrer S., Risau W. Expression of vascular endothelial growth factor during embryonic angiogenesis and endothelial cell differentiation. Development. 1992 Feb;114(2):521–532. doi: 10.1242/dev.114.2.521. [DOI] [PubMed] [Google Scholar]
  6. Breuing K., Eriksson E., Liu P., Miller D. R. Healing of partial thickness porcine skin wounds in a liquid environment. J Surg Res. 1992 Jan;52(1):50–58. doi: 10.1016/0022-4804(92)90278-8. [DOI] [PubMed] [Google Scholar]
  7. Brock T. A., Dvorak H. F., Senger D. R. Tumor-secreted vascular permeability factor increases cytosolic Ca2+ and von Willebrand factor release in human endothelial cells. Am J Pathol. 1991 Jan;138(1):213–221. [PMC free article] [PubMed] [Google Scholar]
  8. Brody I. Dermal and epidermal involvement in the evolution of acute eruptive guttate psoriasis vulgaris. J Invest Dermatol. 1984 May;82(5):465–470. doi: 10.1111/1523-1747.ep12260965. [DOI] [PubMed] [Google Scholar]
  9. Brogi E., Wu T., Namiki A., Isner J. M. Indirect angiogenic cytokines upregulate VEGF and bFGF gene expression in vascular smooth muscle cells, whereas hypoxia upregulates VEGF expression only. Circulation. 1994 Aug;90(2):649–652. doi: 10.1161/01.cir.90.2.649. [DOI] [PubMed] [Google Scholar]
  10. Brown L. F., Asch B., Harvey V. S., Buchinski B., Dvorak H. F. Fibrinogen influx and accumulation of cross-linked fibrin in mouse carcinomas. Cancer Res. 1988 Apr 1;48(7):1920–1925. [PubMed] [Google Scholar]
  11. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Guidi A. J., Dvorak H. F., Senger D. R., Connolly J. L., Schnitt S. J. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in breast cancer. Hum Pathol. 1995 Jan;26(1):86–91. doi: 10.1016/0046-8177(95)90119-1. [DOI] [PubMed] [Google Scholar]
  12. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Manseau E. J., Dvorak H. F., Senger D. R. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol. 1993 Nov;143(5):1255–1262. [PMC free article] [PubMed] [Google Scholar]
  13. Brown L. F., Berse B., Jackman R. W., Tognazzi K., Manseau E. J., Senger D. R., Dvorak H. F. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res. 1993 Oct 1;53(19):4727–4735. [PubMed] [Google Scholar]
  14. Brown L. F., Berse B., Tognazzi K., Manseau E. J., Van de Water L., Senger D. R., Dvorak H. F., Rosen S. Vascular permeability factor mRNA and protein expression in human kidney. Kidney Int. 1992 Dec;42(6):1457–1461. doi: 10.1038/ki.1992.441. [DOI] [PubMed] [Google Scholar]
  15. Brown L. F., Lanir N., McDonagh J., Tognazzi K., Dvorak A. M., Dvorak H. F. Fibroblast migration in fibrin gel matrices. Am J Pathol. 1993 Jan;142(1):273–283. [PMC free article] [PubMed] [Google Scholar]
  16. Brown L. F., Olbricht S. M., Berse B., Jackman R. W., Matsueda G., Tognazzi K. A., Manseau E. J., Dvorak H. F., Van de Water L. Overexpression of vascular permeability factor (VPF/VEGF) and its endothelial cell receptors in delayed hypersensitivity skin reactions. J Immunol. 1995 Mar 15;154(6):2801–2807. [PubMed] [Google Scholar]
  17. Brown L. F., Van de Water L., Harvey V. S., Dvorak H. F. Fibrinogen influx and accumulation of cross-linked fibrin in healing wounds and in tumor stroma. Am J Pathol. 1988 Mar;130(3):455–465. [PMC free article] [PubMed] [Google Scholar]
  18. Brown L. F., Yeo K. T., Berse B., Yeo T. K., Senger D. R., Dvorak H. F., van de Water L. Expression of vascular permeability factor (vascular endothelial growth factor) by epidermal keratinocytes during wound healing. J Exp Med. 1992 Nov 1;176(5):1375–1379. doi: 10.1084/jem.176.5.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Bull R. H., Bates D. O., Mortimer P. S. Intravital video-capillaroscopy for the study of the microcirculation in psoriasis. Br J Dermatol. 1992 May;126(5):436–445. doi: 10.1111/j.1365-2133.1992.tb11815.x. [DOI] [PubMed] [Google Scholar]
  20. Charnock-Jones D. S., Sharkey A. M., Boocock C. A., Ahmed A., Plevin R., Ferrara N., Smith S. K. Vascular endothelial growth factor receptor localization and activation in human trophoblast and choriocarcinoma cells. Biol Reprod. 1994 Sep;51(3):524–530. doi: 10.1095/biolreprod51.3.524. [DOI] [PubMed] [Google Scholar]
  21. Clauss M., Gerlach M., Gerlach H., Brett J., Wang F., Familletti P. C., Pan Y. C., Olander J. V., Connolly D. T., Stern D. Vascular permeability factor: a tumor-derived polypeptide that induces endothelial cell and monocyte procoagulant activity, and promotes monocyte migration. J Exp Med. 1990 Dec 1;172(6):1535–1545. doi: 10.1084/jem.172.6.1535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Colvin R. B., Dvorak H. F. Role of the clotting system in cell-mediated hypersensitivity. II. Kinetics of fibrinogen/fibrin accumulation and vascular permeability changes in tuberculin and cutaneous basophil hypersensitivity reactions. J Immunol. 1975 Jan;114(1 Pt 2):377–387. [PubMed] [Google Scholar]
  23. Conn G., Soderman D. D., Schaeffer M. T., Wile M., Hatcher V. B., Thomas K. A. Purification of a glycoprotein vascular endothelial cell mitogen from a rat glioma-derived cell line. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1323–1327. doi: 10.1073/pnas.87.4.1323. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Connolly D. T., Heuvelman D. M., Nelson R., Olander J. V., Eppley B. L., Delfino J. J., Siegel N. R., Leimgruber R. M., Feder J. Tumor vascular permeability factor stimulates endothelial cell growth and angiogenesis. J Clin Invest. 1989 Nov;84(5):1470–1478. doi: 10.1172/JCI114322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Connolly D. T., Olander J. V., Heuvelman D., Nelson R., Monsell R., Siegel N., Haymore B. L., Leimgruber R., Feder J. Human vascular permeability factor. Isolation from U937 cells. J Biol Chem. 1989 Nov 25;264(33):20017–20024. [PubMed] [Google Scholar]
  26. Cullinan-Bove K., Koos R. D. Vascular endothelial growth factor/vascular permeability factor expression in the rat uterus: rapid stimulation by estrogen correlates with estrogen-induced increases in uterine capillary permeability and growth. Endocrinology. 1993 Aug;133(2):829–837. doi: 10.1210/endo.133.2.8344219. [DOI] [PubMed] [Google Scholar]
  27. Danø K., Andreasen P. A., Grøndahl-Hansen J., Kristensen P., Nielsen L. S., Skriver L. Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res. 1985;44:139–266. doi: 10.1016/s0065-230x(08)60028-7. [DOI] [PubMed] [Google Scholar]
  28. Detmar M., Brown L. F., Claffey K. P., Yeo K. T., Kocher O., Jackman R. W., Berse B., Dvorak H. F. Overexpression of vascular permeability factor/vascular endothelial growth factor and its receptors in psoriasis. J Exp Med. 1994 Sep 1;180(3):1141–1146. doi: 10.1084/jem.180.3.1141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Dolecki G. J., Connolly D. T. Effects of a variety of cytokines and inducing agents on vascular permeability factor mRNA levels in U937 cells. Biochem Biophys Res Commun. 1991 Oct 31;180(2):572–578. doi: 10.1016/s0006-291x(05)81103-9. [DOI] [PubMed] [Google Scholar]
  30. Dvorak H. F., Dvorak A. M., Manseau E. J., Wiberg L., Churchill W. H. Fibrin gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J Natl Cancer Inst. 1979 Jun;62(6):1459–1472. [PubMed] [Google Scholar]
  31. Dvorak H. F., Form D. M., Manseau E. J., Smith B. D. Pathogenesis of desmoplasia. I. Immunofluorescence identification and localization of some structural proteins of line 1 and line 10 guinea pig tumors and of healing wounds. J Natl Cancer Inst. 1984 Nov;73(5):1195–1205. [PubMed] [Google Scholar]
  32. Dvorak H. F., Harvey V. S., Estrella P., Brown L. F., McDonagh J., Dvorak A. M. Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest. 1987 Dec;57(6):673–686. [PubMed] [Google Scholar]
  33. Dvorak H. F., Harvey V. S., McDonagh J. Quantitation of fibrinogen influx and fibrin deposition and turnover in line 1 and line 10 guinea pig carcinomas. Cancer Res. 1984 Aug;44(8):3348–3354. [PubMed] [Google Scholar]
  34. Dvorak H. F., Nagy J. A., Berse B., Brown L. F., Yeo K. T., Yeo T. K., Dvorak A. M., van de Water L., Sioussat T. M., Senger D. R. Vascular permeability factor, fibrin, and the pathogenesis of tumor stroma formation. Ann N Y Acad Sci. 1992 Dec 4;667:101–111. doi: 10.1111/j.1749-6632.1992.tb51603.x. [DOI] [PubMed] [Google Scholar]
  35. Dvorak H. F., Nagy J. A., Dvorak A. M. Structure of solid tumors and their vasculature: implications for therapy with monoclonal antibodies. Cancer Cells. 1991 Mar;3(3):77–85. [PubMed] [Google Scholar]
  36. Dvorak H. F., Nagy J. A., Dvorak J. T., Dvorak A. M. Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules. Am J Pathol. 1988 Oct;133(1):95–109. [PMC free article] [PubMed] [Google Scholar]
  37. Dvorak H. F., Orenstein N. S., Carvalho A. C., Churchill W. H., Dvorak A. M., Galli S. J., Feder J., Bitzer A. M., Rypysc J., Giovinco P. Induction of a fibrin-gel investment: an early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol. 1979 Jan;122(1):166–174. [PubMed] [Google Scholar]
  38. Dvorak H. F., Quay S. C., Orenstein N. S., Dvorak A. M., Hahn P., Bitzer A. M., Carvalho A. C. Tumor shedding and coagulation. Science. 1981 May 22;212(4497):923–924. doi: 10.1126/science.7195067. [DOI] [PubMed] [Google Scholar]
  39. Dvorak H. F., Senger D. R., Dvorak A. M. Fibrin as a component of the tumor stroma: origins and biological significance. Cancer Metastasis Rev. 1983;2(1):41–73. doi: 10.1007/BF00046905. [DOI] [PubMed] [Google Scholar]
  40. Dvorak H. F., Senger D. R., Dvorak A. M., Harvey V. S., McDonagh J. Regulation of extravascular coagulation by microvascular permeability. Science. 1985 Mar 1;227(4690):1059–1061. doi: 10.1126/science.3975602. [DOI] [PubMed] [Google Scholar]
  41. Dvorak H. F., Sioussat T. M., Brown L. F., Berse B., Nagy J. A., Sotrel A., Manseau E. J., Van de Water L., Senger D. R. Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels. J Exp Med. 1991 Nov 1;174(5):1275–1278. doi: 10.1084/jem.174.5.1275. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Dvorak H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986 Dec 25;315(26):1650–1659. doi: 10.1056/NEJM198612253152606. [DOI] [PubMed] [Google Scholar]
  43. Dvorak H. F., Van DeWater L., Bitzer A. M., Dvorak A. M., Anderson D., Harvey V. S., Bach R., Davis G. L., DeWolf W., Carvalho A. C. Procoagulant activity associated with plasma membrane vesicles shed by cultured tumor cells. Cancer Res. 1983 Sep;43(9):4434–4442. [PubMed] [Google Scholar]
  44. Fava R. A., Olsen N. J., Spencer-Green G., Yeo K. T., Yeo T. K., Berse B., Jackman R. W., Senger D. R., Dvorak H. F., Brown L. F. Vascular permeability factor/endothelial growth factor (VPF/VEGF): accumulation and expression in human synovial fluids and rheumatoid synovial tissue. J Exp Med. 1994 Jul 1;180(1):341–346. doi: 10.1084/jem.180.1.341. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Favard C., Moukadiri H., Dorey C., Praloran V., Plouët J. Purification and biological properties of vasculotropin, a new angiogenic cytokine. Biol Cell. 1991;73(1):1–6. doi: 10.1016/0248-4900(91)90002-5. [DOI] [PubMed] [Google Scholar]
  46. Ferrara N., Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem Biophys Res Commun. 1989 Jun 15;161(2):851–858. doi: 10.1016/0006-291x(89)92678-8. [DOI] [PubMed] [Google Scholar]
  47. Ferrara N., Houck K. A., Jakeman L. B., Winer J., Leung D. W. The vascular endothelial growth factor family of polypeptides. J Cell Biochem. 1991 Nov;47(3):211–218. doi: 10.1002/jcb.240470305. [DOI] [PubMed] [Google Scholar]
  48. Ferrara N., Houck K., Jakeman L., Leung D. W. Molecular and biological properties of the vascular endothelial growth factor family of proteins. Endocr Rev. 1992 Feb;13(1):18–32. doi: 10.1210/edrv-13-1-18. [DOI] [PubMed] [Google Scholar]
  49. Finkenzeller G., Marmé D., Weich H. A., Hug H. Platelet-derived growth factor-induced transcription of the vascular endothelial growth factor gene is mediated by protein kinase C. Cancer Res. 1992 Sep 1;52(17):4821–4823. [PubMed] [Google Scholar]
  50. Folkman J., Shing Y. Angiogenesis. J Biol Chem. 1992 Jun 5;267(16):10931–10934. [PubMed] [Google Scholar]
  51. Gerlowski L. E., Jain R. K. Microvascular permeability of normal and neoplastic tissues. Microvasc Res. 1986 May;31(3):288–305. doi: 10.1016/0026-2862(86)90018-x. [DOI] [PubMed] [Google Scholar]
  52. Gitay-Goren H., Halaban R., Neufeld G. Human melanoma cells but not normal melanocytes express vascular endothelial growth factor receptors. Biochem Biophys Res Commun. 1993 Feb 15;190(3):702–708. doi: 10.1006/bbrc.1993.1106. [DOI] [PubMed] [Google Scholar]
  53. Goldberg M. A., Schneider T. J. Similarities between the oxygen-sensing mechanisms regulating the expression of vascular endothelial growth factor and erythropoietin. J Biol Chem. 1994 Feb 11;269(6):4355–4359. [PubMed] [Google Scholar]
  54. Gospodarowicz D., Abraham J. A., Schilling J. Isolation and characterization of a vascular endothelial cell mitogen produced by pituitary-derived folliculo stellate cells. Proc Natl Acad Sci U S A. 1989 Oct;86(19):7311–7315. doi: 10.1073/pnas.86.19.7311. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Haddow A. Molecular repair, wound healing, and carcinogenesis: tumor production a possible overhealing? Adv Cancer Res. 1972;16:181–234. doi: 10.1016/s0065-230x(08)60341-3. [DOI] [PubMed] [Google Scholar]
  56. Heuser L. S., Miller F. N. Differential macromolecular leakage from the vasculature of tumors. Cancer. 1986 Feb 1;57(3):461–464. doi: 10.1002/1097-0142(19860201)57:3<461::aid-cncr2820570310>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  57. Houck K. A., Ferrara N., Winer J., Cachianes G., Li B., Leung D. W. The vascular endothelial growth factor family: identification of a fourth molecular species and characterization of alternative splicing of RNA. Mol Endocrinol. 1991 Dec;5(12):1806–1814. doi: 10.1210/mend-5-12-1806. [DOI] [PubMed] [Google Scholar]
  58. Houck K. A., Leung D. W., Rowland A. M., Winer J., Ferrara N. Dual regulation of vascular endothelial growth factor bioavailability by genetic and proteolytic mechanisms. J Biol Chem. 1992 Dec 25;267(36):26031–26037. [PubMed] [Google Scholar]
  59. Jackson M. R., Carney E. W., Lye S. J., Ritchie J. W. Localization of two angiogenic growth factors (PDECGF and VEGF) in human placentae throughout gestation. Placenta. 1994 Jun;15(4):341–353. doi: 10.1016/0143-4004(94)90002-7. [DOI] [PubMed] [Google Scholar]
  60. Koch A. E., Harlow L. A., Haines G. K., Amento E. P., Unemori E. N., Wong W. L., Pope R. M., Ferrara N. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. 1994 Apr 15;152(8):4149–4156. [PubMed] [Google Scholar]
  61. Kohn S., Nagy J. A., Dvorak H. F., Dvorak A. M. Pathways of macromolecular tracer transport across venules and small veins. Structural basis for the hyperpermeability of tumor blood vessels. Lab Invest. 1992 Nov;67(5):596–607. [PubMed] [Google Scholar]
  62. Ladoux A., Frelin C. Hypoxia is a strong inducer of vascular endothelial growth factor mRNA expression in the heart. Biochem Biophys Res Commun. 1993 Sep 15;195(2):1005–1010. doi: 10.1006/bbrc.1993.2144. [DOI] [PubMed] [Google Scholar]
  63. Lanir N., Ciano P. S., Van de Water L., McDonagh J., Dvorak A. M., Dvorak H. F. Macrophage migration in fibrin gel matrices. II. Effects of clotting factor XIII, fibronectin, and glycosaminoglycan content on cell migration. J Immunol. 1988 Apr 1;140(7):2340–2349. [PubMed] [Google Scholar]
  64. Leung D. W., Cachianes G., Kuang W. J., Goeddel D. V., Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science. 1989 Dec 8;246(4935):1306–1309. doi: 10.1126/science.2479986. [DOI] [PubMed] [Google Scholar]
  65. Maglione D., Guerriero V., Viglietto G., Delli-Bovi P., Persico M. G. Isolation of a human placenta cDNA coding for a protein related to the vascular permeability factor. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9267–9271. doi: 10.1073/pnas.88.20.9267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  66. Matthews W., Jordan C. T., Gavin M., Jenkins N. A., Copeland N. G., Lemischka I. R. A receptor tyrosine kinase cDNA isolated from a population of enriched primitive hematopoietic cells and exhibiting close genetic linkage to c-kit. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9026–9030. doi: 10.1073/pnas.88.20.9026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Midy V., Plouët J. Vasculotropin/vascular endothelial growth factor induces differentiation in cultured osteoblasts. Biochem Biophys Res Commun. 1994 Feb 28;199(1):380–386. doi: 10.1006/bbrc.1994.1240. [DOI] [PubMed] [Google Scholar]
  68. Millauer B., Wizigmann-Voos S., Schnürch H., Martinez R., Møller N. P., Risau W., Ullrich A. High affinity VEGF binding and developmental expression suggest Flk-1 as a major regulator of vasculogenesis and angiogenesis. Cell. 1993 Mar 26;72(6):835–846. doi: 10.1016/0092-8674(93)90573-9. [DOI] [PubMed] [Google Scholar]
  69. Moor R. M., Seamark R. F. Cell signaling, permeability, and microvasculatory changes during antral follicle development in mammals. J Dairy Sci. 1986 Mar;69(3):927–943. doi: 10.3168/jds.S0022-0302(86)80482-9. [DOI] [PubMed] [Google Scholar]
  70. Myoken Y., Kayada Y., Okamoto T., Kan M., Sato G. H., Sato J. D. Vascular endothelial cell growth factor (VEGF) produced by A-431 human epidermoid carcinoma cells and identification of VEGF membrane binding sites. Proc Natl Acad Sci U S A. 1991 Jul 1;88(13):5819–5823. doi: 10.1073/pnas.88.13.5819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Nagy J. A., Masse E. M., Herzberg K. T., Meyers M. S., Yeo K. T., Yeo T. K., Sioussat T. M., Dvorak H. F. Pathogenesis of ascites tumor growth: vascular permeability factor, vascular hyperpermeability, and ascites fluid accumulation. Cancer Res. 1995 Jan 15;55(2):360–368. [PubMed] [Google Scholar]
  72. Nagy J. A., Morgan E. S., Herzberg K. T., Manseau E. J., Dvorak A. M., Dvorak H. F. Pathogenesis of ascites tumor growth: angiogenesis, vascular remodeling, and stroma formation in the peritoneal lining. Cancer Res. 1995 Jan 15;55(2):376–385. [PubMed] [Google Scholar]
  73. O'Connor S. W., Bale W. F. Accessibility of circulating immunoglobulin G to the extravascular compartment of solid rat tumors. Cancer Res. 1984 Sep;44(9):3719–3723. [PubMed] [Google Scholar]
  74. Okuda Y., Okamura H., Kanzaki H., Takenaka A., Morimoto K., Nishimura T. [An ultrastructural study of capillary permeability of rabbit ovarian follicles during ovulation using carbon tracer (author's transl)]. Nihon Sanka Fujinka Gakkai Zasshi. 1980 Jul;32(7):859–867. [PubMed] [Google Scholar]
  75. Parent D., Bernard B. A., Desbas C., Heenen M., Darmon M. Y. Spreading of psoriatic plaques: alteration of epidermal differentiation precedes capillary leakiness and anomalies in vascular morphology. J Invest Dermatol. 1990 Sep;95(3):333–340. doi: 10.1111/1523-1747.ep12485084. [DOI] [PubMed] [Google Scholar]
  76. Park J. E., Keller G. A., Ferrara N. The vascular endothelial growth factor (VEGF) isoforms: differential deposition into the subepithelial extracellular matrix and bioactivity of extracellular matrix-bound VEGF. Mol Biol Cell. 1993 Dec;4(12):1317–1326. doi: 10.1091/mbc.4.12.1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Payer A. F. Permeability of ovarian follicles and capillaries in mice. Am J Anat. 1975 Mar;142(3):295–317. doi: 10.1002/aja.1001420303. [DOI] [PubMed] [Google Scholar]
  78. Pepper M. S., Ferrara N., Orci L., Montesano R. Vascular endothelial growth factor (VEGF) induces plasminogen activators and plasminogen activator inhibitor-1 in microvascular endothelial cells. Biochem Biophys Res Commun. 1991 Dec 16;181(2):902–906. doi: 10.1016/0006-291x(91)91276-i. [DOI] [PubMed] [Google Scholar]
  79. Pertovaara L., Kaipainen A., Mustonen T., Orpana A., Ferrara N., Saksela O., Alitalo K. Vascular endothelial growth factor is induced in response to transforming growth factor-beta in fibroblastic and epithelial cells. J Biol Chem. 1994 Mar 4;269(9):6271–6274. [PubMed] [Google Scholar]
  80. Phillips H. S., Hains J., Leung D. W., Ferrara N. Vascular endothelial growth factor is expressed in rat corpus luteum. Endocrinology. 1990 Aug;127(2):965–967. doi: 10.1210/endo-127-2-965. [DOI] [PubMed] [Google Scholar]
  81. Plate K. H., Breier G., Weich H. A., Risau W. Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo. Nature. 1992 Oct 29;359(6398):845–848. doi: 10.1038/359845a0. [DOI] [PubMed] [Google Scholar]
  82. Plouët J., Schilling J., Gospodarowicz D. Isolation and characterization of a newly identified endothelial cell mitogen produced by AtT-20 cells. EMBO J. 1989 Dec 1;8(12):3801–3806. doi: 10.1002/j.1460-2075.1989.tb08557.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Quinn T. P., Peters K. G., De Vries C., Ferrara N., Williams L. T. Fetal liver kinase 1 is a receptor for vascular endothelial growth factor and is selectively expressed in vascular endothelium. Proc Natl Acad Sci U S A. 1993 Aug 15;90(16):7533–7537. doi: 10.1073/pnas.90.16.7533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Rippe B., Haraldsson B. Transport of macromolecules across microvascular walls: the two-pore theory. Physiol Rev. 1994 Jan;74(1):163–219. doi: 10.1152/physrev.1994.74.1.163. [DOI] [PubMed] [Google Scholar]
  85. Salo O. P., Kousa M., Mustakallio K. K., Lassus A. Demonstration of fibrin in skin diseases. II. Psoriasis. Acta Derm Venereol. 1972;52(4):295–297. [PubMed] [Google Scholar]
  86. Senger D. R., Connolly D. T., Van de Water L., Feder J., Dvorak H. F. Purification and NH2-terminal amino acid sequence of guinea pig tumor-secreted vascular permeability factor. Cancer Res. 1990 Mar 15;50(6):1774–1778. [PubMed] [Google Scholar]
  87. Senger D. R., Galli S. J., Dvorak A. M., Perruzzi C. A., Harvey V. S., Dvorak H. F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science. 1983 Feb 25;219(4587):983–985. doi: 10.1126/science.6823562. [DOI] [PubMed] [Google Scholar]
  88. Senger D. R., Perruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res. 1986 Nov;46(11):5629–5632. [PubMed] [Google Scholar]
  89. Senger D. R., Van de Water L., Brown L. F., Nagy J. A., Yeo K. T., Yeo T. K., Berse B., Jackman R. W., Dvorak A. M., Dvorak H. F. Vascular permeability factor (VPF, VEGF) in tumor biology. Cancer Metastasis Rev. 1993 Sep;12(3-4):303–324. doi: 10.1007/BF00665960. [DOI] [PubMed] [Google Scholar]
  90. Sharkey A. M., Charnock-Jones D. S., Boocock C. A., Brown K. D., Smith S. K. Expression of mRNA for vascular endothelial growth factor in human placenta. J Reprod Fertil. 1993 Nov;99(2):609–615. doi: 10.1530/jrf.0.0990609. [DOI] [PubMed] [Google Scholar]
  91. Sharma H. S., Wünsch M., Schmidt M., Schott R. J., Kandolf R., Schaper W. Expression of angiogenic growth factors in the collateralized swine myocardium. EXS. 1992;61:255–260. doi: 10.1007/978-3-0348-7001-6_40. [DOI] [PubMed] [Google Scholar]
  92. Shifren J. L., Doldi N., Ferrara N., Mesiano S., Jaffe R. B. In the human fetus, vascular endothelial growth factor is expressed in epithelial cells and myocytes, but not vascular endothelium: implications for mode of action. J Clin Endocrinol Metab. 1994 Jul;79(1):316–322. doi: 10.1210/jcem.79.1.8027247. [DOI] [PubMed] [Google Scholar]
  93. Shweiki D., Itin A., Neufeld G., Gitay-Goren H., Keshet E. Patterns of expression of vascular endothelial growth factor (VEGF) and VEGF receptors in mice suggest a role in hormonally regulated angiogenesis. J Clin Invest. 1993 May;91(5):2235–2243. doi: 10.1172/JCI116450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  94. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992 Oct 29;359(6398):843–845. doi: 10.1038/359843a0. [DOI] [PubMed] [Google Scholar]
  95. Sioussat T. M., Dvorak H. F., Brock T. A., Senger D. R. Inhibition of vascular permeability factor (vascular endothelial growth factor) with antipeptide antibodies. Arch Biochem Biophys. 1993 Feb 15;301(1):15–20. doi: 10.1006/abbi.1993.1109. [DOI] [PubMed] [Google Scholar]
  96. Staberg B., Worm A. M., Klemp P., Rossing N. Transvascular transport and distribution of fluid and protein in psoriasis. J Am Acad Dermatol. 1983 Feb;8(2):193–199. doi: 10.1016/s0190-9622(83)80182-0. [DOI] [PubMed] [Google Scholar]
  97. Terman B. I., Carrion M. E., Kovacs E., Rasmussen B. A., Eddy R. L., Shows T. B. Identification of a new endothelial cell growth factor receptor tyrosine kinase. Oncogene. 1991 Sep;6(9):1677–1683. [PubMed] [Google Scholar]
  98. Terman B. I., Dougher-Vermazen M., Carrion M. E., Dimitrov D., Armellino D. C., Gospodarowicz D., Böhlen P. Identification of the KDR tyrosine kinase as a receptor for vascular endothelial cell growth factor. Biochem Biophys Res Commun. 1992 Sep 30;187(3):1579–1586. doi: 10.1016/0006-291x(92)90483-2. [DOI] [PubMed] [Google Scholar]
  99. Tischer E., Gospodarowicz D., Mitchell R., Silva M., Schilling J., Lau K., Crisp T., Fiddes J. C., Abraham J. A. Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family. Biochem Biophys Res Commun. 1989 Dec 29;165(3):1198–1206. doi: 10.1016/0006-291x(89)92729-0. [DOI] [PubMed] [Google Scholar]
  100. Tischer E., Mitchell R., Hartman T., Silva M., Gospodarowicz D., Fiddes J. C., Abraham J. A. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991 Jun 25;266(18):11947–11954. [PubMed] [Google Scholar]
  101. Underwood J. C., Carr I. The ultrastructure and permeability characteristics of the blood vessels of a transplantable rat sarcoma. J Pathol. 1972 Jul;107(3):157–166. doi: 10.1002/path.1711070303. [DOI] [PubMed] [Google Scholar]
  102. Unemori E. N., Ferrara N., Bauer E. A., Amento E. P. Vascular endothelial growth factor induces interstitial collagenase expression in human endothelial cells. J Cell Physiol. 1992 Dec;153(3):557–562. doi: 10.1002/jcp.1041530317. [DOI] [PubMed] [Google Scholar]
  103. Vaisman N., Gospodarowicz D., Neufeld G. Characterization of the receptors for vascular endothelial growth factor. J Biol Chem. 1990 Nov 15;265(32):19461–19466. [PubMed] [Google Scholar]
  104. Wilting J., Christ B., Weich H. A. The effects of growth factors on the day 13 chorioallantoic membrane (CAM): a study of VEGF165 and PDGF-BB. Anat Embryol (Berl) 1992 Aug;186(3):251–257. doi: 10.1007/BF00174147. [DOI] [PubMed] [Google Scholar]
  105. Worm A. M., Rossing N. Microvascular protein leakage in extensive skin diseases: aspects of the transport mechanisms. J Invest Dermatol. 1980 Oct;75(4):302–305. doi: 10.1111/1523-1747.ep12530896. [DOI] [PubMed] [Google Scholar]
  106. Yayon A., Klagsbrun M., Esko J. D., Leder P., Ornitz D. M. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991 Feb 22;64(4):841–848. doi: 10.1016/0092-8674(91)90512-w. [DOI] [PubMed] [Google Scholar]
  107. Yeo K. T., Wang H. H., Nagy J. A., Sioussat T. M., Ledbetter S. R., Hoogewerf A. J., Zhou Y., Masse E. M., Senger D. R., Dvorak H. F. Vascular permeability factor (vascular endothelial growth factor) in guinea pig and human tumor and inflammatory effusions. Cancer Res. 1993 Jun 15;53(12):2912–2918. [PubMed] [Google Scholar]
  108. Yeo T. K., Brown L., Dvorak H. F. Alterations in proteoglycan synthesis common to healing wounds and tumors. Am J Pathol. 1991 Jun;138(6):1437–1450. [PMC free article] [PubMed] [Google Scholar]
  109. Yeo T. K., Senger D. R., Dvorak H. F., Freter L., Yeo K. T. Glycosylation is essential for efficient secretion but not for permeability-enhancing activity of vascular permeability factor (vascular endothelial growth factor). Biochem Biophys Res Commun. 1991 Sep 30;179(3):1568–1575. doi: 10.1016/0006-291x(91)91752-x. [DOI] [PubMed] [Google Scholar]
  110. de Vries C., Escobedo J. A., Ueno H., Houck K., Ferrara N., Williams L. T. The fms-like tyrosine kinase, a receptor for vascular endothelial growth factor. Science. 1992 Feb 21;255(5047):989–991. doi: 10.1126/science.1312256. [DOI] [PubMed] [Google Scholar]

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